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The Role of Epidemiology in Understanding the Health Effects of Helicobacter pylori

Helicobacter pylori infects one-half or more of the world population and causes chronic gastritis, peptic ulcer, and probably gastric cancer as well. The public-health impact of this infection is far from trivial. Chronic gastritis and peptic ulcer disease are common across populations. Gastric cancer rates have declined during this century, but this cancer remains second among causes of cancer deaths worldwide. Much has been learned about biological and clinical aspects of H. pylori, but key epidemiologic questions have not been answered. How infection results in diverse diseases, the precise modes of transmission, and a comprehensive solution to H. pylori as a public-health problem remain elusive. In this paper, we highlight methodologic challenges and outline an agenda for future research. Challenges include improving validation of detection methods and considering the limitations of these methods when interpreting epidemiologic data. The role of cofactors in H. pylori-induced diseases requires extensive exploration. Many intriguing areas of H. pylori research require the skills of epidemiologists. The discovery of an infectious etiology of common chronic diseases presents a promising opportunity for improving public health.

From the 1School of Public Health, University of Texas–Houston Health Science Center and 2Department of Preventive Medicine, University of Southern California, Los Angeles.

The incidental discovery in 1983 1,2 of a bacterium that infects one-half or more of the world population 3 proved to have profound public-health implications. 4,5 We know now that Helicobacter pylori causes chronic gastritis, peptic ulcer, and probably gastric cancer as well. 6,7 Chronic gastritis and peptic ulcer disease are common, particularly among the elderly and low-income groups. 8–10 Gastric cancer remains second among causes of cancer deaths worldwide 11 despite declining occurrence during this century. 10 In the United States, annual direct costs of H. pylori-associated diseases exceed five billion dollars. 12 Much has been learned about biological and clinical aspects of H. pylori, but key epidemiologic questions have not been answered. Published reviews have effectively summarized the epidemiologic literature. 13–17 Our aim is to highlight methodologic challenges and outline an agenda for future research. In this way, we hope to stimulate interest in the many intriguing areas of H. pylori research that require the skills of epidemiologists.

Challenges

Natural History

A major challenge to epidemiologic studies of H. pylori comes from difficulty in detecting cases at onset. 18 Acute infection has been described in a few instances of experimental and accidental inoculation. 19,20 In these cases, H. pylori colonization produced inflammation of the gastric mucosa accompanied by a broad spectrum of dyspeptic symptoms. Two experimental inoculations led to distinct outcomes. 20 The first resulted in symptomatic acute gastritis with detectable H. pylori on histologic examination of biopsies; the infection appeared to be eliminated by host defenses before 14 days, when a 1-week course of tinidazole was taken 19; no short- or long-term antibody response was detected. 20 The second voluntary inoculation resulted in a persistent infection, which was resistant to a series of monodrug therapies. 20

In the case of experimentally acquired persistent infection, immunoglobulin (Ig) M levels rose and fell within weeks after acute infection; IgG became detectable after normalization of IgM. 14 Several studies have followed IgG levels after successful anti-H. pylori therapy; in general, titers decline after elimination of H. pylori, often reaching seronegative levels within a year or two. 21–24 The immune response to H. pylori may not confer immunity, given that previously infected individuals are susceptible to reinfection. 25 Infection with one strain may not prevent infection by others, because coinfection with multiple strains is common. 26

Because spontaneous elimination is rarely observed when adults with prevalent infection are followed over time, it has been assumed that infection generally persists once acquired. 13,17 This assumption, however, contradicts evidence that H. pylori may result in either brief, self-limiting infection or persistent infection. 19,27 In fact, because infection is not generally detected at onset, the proportion of acute infections that persist is not known. Furthermore, cases of infection detected in epidemiologic studies will tend to be persistent ones, particularly when measurement of antibodies is used for detection. Thus, most of what we know about the epidemiology of H. pylori infection relates to persistent infection; little is known about acute infection.

Detection of H. pylori

H. pylori detection methods include invasive procedures, which require gastric biopsy, and noninvasive tests, which measure indicators of infection and are suited to epidemiologic studies. 28 The method used most widely in epidemiologic research to date is the enzyme immunoassay to detect IgG antibodies. Therefore, most evidence of H. pylori occurrence comes from seroprevalence studies. The interpretation of serostatus is problematic, because elevated antibody levels may reflect either an active or an eradicated infection, whereas undetectable antibody levels can occur in someone who was previously infected, has recently become infected, or has never been infected. Beyond the ambiguous relation between serostatus and infection status, the accuracy of specific serologic assays in measuring antibody levels may vary across populations. 29 In addition, serology has limited usefulness in very young children, 30 who may be slow to mount a detectable antibody response 31 and, in the case of infants, may have maternal antibodies. 32

The noninvasive urea breath test detects H. pylori urease activity in the stomach and thus accurately detects active infection 33; however, limited validation has been conducted in children under 10 years of age. It is not known whether the breath test detects acute and persistent infection equally well. Breath tests have not been used extensively in epidemiologic research, because they cost more than serologic tests, although they have proven feasible in population-based studies. 34–38 A stool antigen test has been introduced, 39,40 but its usefulness in epidemiologic research has not yet been established. Validating H. pylori detection methods in populations of epidemiologic interest is problematic, because there is no gold standard diagnostic method 25 that can be used in groups of healthy individuals.

H. pylori Prevalence

Numerous studies reveal wide ranges in prevalence around the world 14,41 and link prevalent infection to poor socioeconomic conditions and residential overcrowding. 14 Much evidence suggests that persistent infections are most often acquired in childhood. 14 To date, most studies that have identified risk factors for infection have been cross-sectional; in general, reports from these studies overlook the inability of this design to differentiate factors that influence acquisition of infection from those that influence persistence. Thus, we do not know whether identified H. pylori “risk factors” predict susceptibility to acute infection, persistent infection, or both.

H. pylori Incidence

Knowledge of H. pylori incidence must be inferred from studies that follow individuals over time and repeatedly measure prevalent infection. 18 Numerous studies have examined recurrence after confirmed eradication of infection. 42 Inferring risk of reinfection from such studies is problematic, because it is difficult to determine whether recurrence represents reinfection or recrudescence of an infection that was suppressed to undetectable levels but was not cured. 43 Identification of the same strain before and after treatment has been offered as evidence of recrudescence, 42 given the diversity of H. pylori strains in series of unrelated patients. 42,44 But identical strains have been observed in some family members, 45,46 and isolation of a new strain may represent a preexisting coinfection.

Historical cohort studies using stored sera from adults have reported seroconversion rates from 0.3% to 1.0% per year and seroreversion rates from 1.2% to 1.6% per year. 47–50 These studies examined infection status at two or three time points over intervals of many years. The low rates of change observed could be due entirely to test error. 3 Therefore, conclusions regarding the relative frequency of conversion and reversion are problematic. Also, such studies may miss infections that do not result in persistent detectable antibodies, thus underestimating incidence rates.

Cohort studies covering diverse age ranges have followed H. pylori infection in healthy children, some at several time points. 51 These studies estimate a wide range of incidence rates, from 0.1% per year to 13% per month, with higher rates occurring in populations of low socioeconomic status. In some demographic subgroups, frequent loss of infection occurred. As with the adult studies, the contribution of test error to observed changes in status has not been evaluated. In addition, information on variations in incidence over defined childhood age intervals is sparse.

Transmission Pathways

The means by which H. pylori spreads in populations is not fully clear. 14 The organism is not easily isolated from extragastric secretions, so ambiguity persists regarding the usual portals of exit. 15 Perinatal transmission from mother to infant does not appear to occur, 32,52 and blood-borne transmission is implausible. Iatrogenic transmission by gastroenterologic procedures has been documented, 14 but other specific modes of transmission have been neither confirmed nor ruled out. Direct person-to-person transmission is probable, but the relative importance of fecal-oral, oral-oral, and what has been called gastric-oral 53 (through vomitus) routes is not apparent. Few investigations have focused on host conditions that may facilitate transmission. For example, a recent experimental study isolated H. pylori from induced vomitus and cathartic stools, suggesting that acute gastrointestinal illness may play a role in bacterial shedding. 53

Disease Pathways

The major disease pathways resulting from H. pylori infection have been described, 54 but little is known about what determines one pathway or another. 55 Some evidence suggests that characteristics of bacterial 56–60 or host 61 genetics may influence the disease outcome. Data on cofactors in ulcer or cancer etiology are limited, however.

Peptic Ulcer

The causal relation between H. pylori and peptic ulcer was established by a 1994 consensus panel convened by the National Institutes of Health. 6 It has been estimated that 10–20% of H. pylori- infected persons will develop a peptic ulcer in their lifetime. 62 Host factors including smoking, heavy alcohol use, stress, poor sleep and eating habits, hard physical labor, and genetic susceptibility may influence ulcer risk, 62,63 but it is not clear whether any of these factors modifies the risk of peptic ulcer given H. pylori infection.

Gastric Cancer

Before the relation between H. pylori and gastric cancer was discovered, Correa 64 synthesized epidemiologic and biomedical evidence into a model that presented gastric carcinoma as the result of a multistage degenerative process beginning with chronic gastritis. After being identified as a cause of chronic gastritis, H. pylori fit coherently in this model. 65 Evidence from epidemiologic studies, however, has been inconsistent. 66 Many standard case-control studies have investigated the H. pylori-gastric carcinoma association, 67 but this design is believed to underestimate the relative risk, because precancerous changes promote loss of H. pylori colonization. 68 Nested case-control studies conducted from cohorts with stored sera have been more compelling, 67 although the precancerous process may eliminate the infection some years before cancer diagnosis, 68 so the degree of misclassification of antecedent infection status in cancer cases depends on the time interval between serum collection and diagnosis. Combined data from the first three such nested studies revealed an increase in the estimated odds ratio for H. pylori seropositivity and subsequent gastric carcinoma from 2.1, when serum was collected 0–4 years before cancer diagnosis, to 4.4 and 8.7 when serum was collected 10–14 and 15 or more years before diagnosis, respectively. 68 Recent meta-analyses have reported summary relative risk estimates from nested studies of 2.2 69 and 2.5. 67 These estimates overlook documented sources of variation in effect, including age and stage at diagnosis, anatomic subsite, follow-up interval, and both the gastric cancer incidence rates and the prevalence of H. pylori infection in the local population. 66,68,69

Most studies of H. pylori and gastric cancer have not adjusted adequately for gastric cancer risk factors, 66,67 many of which may similarly influence H. pylori infection 14,70–72; thus, the relative risk estimates for H. pylori and gastric cancer may be biased upward. The extent to which upward bias from confounding balances downward bias from differential misclassification due to loss of H. pylori colonization in cancer cases is not clear. Nondifferential errors from antibody tests most likely contribute to underestimation of the effect.

A rare gastric cancer subtype, mucosa-associated lymphoid tissue lymphoma, arises in the presence of H. pylori- induced gastritis. 73 Elimination of H. pylori infection results in complete remission of most low-grade mucosa-associated lymphoid tissue lymphomas. 73 Evidence from intervention studies is not yet available for gastric carcinoma. Randomized intervention trials in Europe, Latin America, China, and Japan aim to determine whether H. pylori elimination prevents carcinoma or progression of precancerous lesions. 74 The first of these trials completed follow-up in 1998, and findings are beginning to emerge. 75 It remains to be seen whether the design of these trials in terms of size, timing of follow-up, and effectiveness of interventions 76,77 will lead to definitive answers.

Gastroesophageal Disease

H. pylori does not appear to increase the risk of adenocarcinoma of either the esophagus 78 or the gastric cardia, 69 although the role of the infection in gastroesophageal disease remains unclear. 79,80 In cross-sectional studies, H. pylori is not related to increased gastroesophageal reflux disease 79,80; however, an increased risk of reflux disease has been observed in duodenal ulcer patients after eradication of H. pylori infection, 79 leading to the hypothesis that the bacteria protect against reflux disease. 81 Alternately, confounding influences related to ulcer healing have been proposed to explain the paradox. 79,80

Other Diseases

Obstacles to Prevention

Table 1 summarizes obstacles to the development of control measures for H. pylori infection. The means of interrupting transmission are unclear, owing to inadequate knowledge of the natural history, modes of transmission, and host susceptibility factors. Cure of H. pylori infection requires compliance with burdensome multidrug regimens that are least effective where infection is most prevalent, owing to antibiotic resistance and other complicating factors. 25,87 The potential for developing an effective vaccine remains unknown. Stimulated immunity has been achieved in mouse models developed for vaccine research, 88 but human vaccine trials have not yet been successful. 28

On the other hand, optimal anti-H. pylori therapies work effectively for most adults in developed countries, 25 where the probability of reacquiring a persistent infection is low 18; the same may apply in some developing country settings. Assuming a causal association, cost-effectiveness analysis based on U.S. data suggests that screening and treating older adults may be a reasonable strategy for gastric cancer prevention, with the added benefit of preventing other H. pylori-associated diseases. 89 At the same time, the suggestion that H. pylori eradication may increase the occurrence of gastroesophageal diseases has raised cautions regarding the benefits of H. pylori eradication as a disease-prevention strategy. 81 Intervention trials are needed to evaluate the effectiveness and adverse consequences of such a strategy.

Research Agenda

The Role of Epidemiology

In an editorial written on the occasion of the 1994 National Institutes of Health consensus, 6 Peura and Graham state, “It is amazing that this major problem of mankind was largely defined and solved by clinical gastroenterologists essentially without support from the biomedical research establishment. Even now, it is apparent that we are not dealing with a mystery such as the cause of pancreatic cancer, but with an infection that can be cured or prevented. It is time that our biomedical research establishment tempers its traditional focus on molecular mechanisms of disease...Increased emphasis must be placed on improving H. pylori therapy, understanding its mode of transmission, searching for weak links in the transmission chain, and asking whether vaccination is a practical means of preventing infection. Childhood appears to be the time of greatest risk of acquiring infection, and yet no studies are being done to examine why this is or how to prevent this from happening.”90,p.1139

Peura and Graham 90 delineated research questions that require the expertise of epidemiologists; however, little progress has been made in addressing these questions since 1994. Current obstacles to H. pylori prevention present a challenge to epidemiologists and other disease control experts. Furthermore, the etiologic role of H. pylori infection in associated diseases remains poorly understood. Working with scientists from other disciplines, epidemiologists can help identify determinants of H. pylori disease pathways and strategies for prevention.

We propose a research agenda for H. pylori epidemiology (Table 2). Epidemiologists can help generate the knowledge required to develop prevention strategies for infection and subsequent disease. A critical aim is to understand better how infection induces diverse diseases. Methodologic challenges stem largely from difficulties in the measurement of H. pylori status. These challenges require improved validation of detection methods across demographic groups as well as consideration of the limitations of detection methods when interpreting epidemiologic data. Finally, the role of cofactors in H. pylori-induced diseases requires extensive exploration. The discovery of an infectious etiology of common chronic digestive diseases presents a promising opportunity for improving public health. The methodologic challenges inherent in H. pylori research warrant increased attention from epidemiologists.

7. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Cancer Risks to Humans. vol. 61. Schistosomes, Liver Flukes and Helicobacter pylori. Lyon: International Agency for Research on Cancer, 1994.